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P15 - Role of kinase-coupled TRP channels in Mg2+ homeostasis: From mouse models to human disease

TRPM6 and TRPM7 are bifunctional proteins comprising a TRP channel segment linked to an α-type protein kinase. Loss-of-function mutations in the human TRPM6 gene cause an autosomal recessive disorder, hypomagnesemia with secondary hypocalcemia (HSH). In addition, point mutations in the human TRPM7 gene lead to impaired thrombopoiesis due to altered cellular Mg2+ metabolism and cytoskeletal architecture. Mechanistically, however, the in vivo roles of TRPM6 and TRPM7 remain incompletely understood. In the present project, we aim to define the (patho)physiological role of TRPM7. The function of TRPM7 will be assessed by single channel analysis of TRPM7, phenotyping of TRPM7-deficient cells in conjunction with metabolic and proteomic profiling of mice carrying tissue-specific null mutations in Trpm7 and animals with a global ‘kinase-dead’ point mutation in the gene. Overall, the suggested project will grant deeper insight into the poorly understood roles of the kinase-coupled channels in whole-body homeostasis.